Antiviral immunity rewired for axon regeneration
Authors: Meng Jiang, Wenwen Zeng
Journal: Cell Reports Medicine (2023)

In Neuron’s January 18th issue, Wang et al.1Wang X. Yang C. Wang X. Miao J. Chen W. Zhou Y. Xu Y. An Y. Cheng A. Ye W. et al.Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis.Neuron. 2022; 111https://doi.org/10.1016/j.neuron.2022.10.028Abstract Full Text Full Text PDF Scopus (1) Google Scholar report that activating the immune signaling IFNγ-cGAS-STING axis promotes axon regeneration in both the peripheral and central nervous systems. Their findings uncover the coordination mechanism of neural innate immune responses for axon regeneration. In Neuron’s January 18th issue, Wang et al.1Wang X. Yang C. Wang X. Miao J. Chen W. Zhou Y. Xu Y. An Y. Cheng A. Ye W. et al.Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis.Neuron. 2022; 111https://doi.org/10.1016/j.neuron.2022.10.028Abstract Full Text Full Text PDF Scopus (1) Google Scholar report that activating the immune signaling IFNγ-cGAS-STING axis promotes axon regeneration in both the peripheral and central nervous systems. Their findings uncover the coordination mechanism of neural innate immune responses for axon regeneration. Traumatic injury in the adult central nervous system (CNS) can lead to devastating consequences such as paralysis. Axon regeneration is manifested as the process of axon regrowth and the subsequent re-innervation of target regions following injury. In contrast to the limited axonal regeneration capacity of the CNS, such as retinal ganglion cells (RGCs), the peripheral nervous system (PNS) exemplified by dorsal root ganglion cells (DRGs) is capable of regenerating axons after nerve damage. Therefore, the distinct and shared machinery has been intensively interrogated to inform the therapeutic strategies in the CNS. Mammalian target of rapamycin (mTOR), signal transducers and activators of transcription 3 (STAT3), suppressor of cytokine signaling 3 (SOCS3, a negative regulator of Janus kinase/STAT pathway), and phosphatase and tensin homologue (PTEN, a negative regulator of mTOR and STAT3) represent such outstanding candidates identified.2Sun F. Park K.K. Belin S. Wang D. Lu T. Chen G. Zhang K. Yeung C. Feng G. Yankner B.A. He Z. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3.Nature. 2011; 480: 372-375https://doi.org/10.1038/nature10594Crossref PubMed Scopus (523) Google Scholar,3Varadarajan S.G. Hunyara J.L. Hamilton N.R. Kolodkin A.L. Huberman A.D. Central nervous system regeneration.Cell. 2022; 185: 77-94https://doi.org/10.1016/j.cell.2021.10.029Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar In parallel, innate immune responses have been primarily studied for their protective roles against pathogen invasions. However, recent studies have unveiled that the neural immune response is elicited upon nerve damage and is critically involved in nerve repair and injury-associated pathophysiology. For instance, the cGAS-STING signaling axis, comprising the synthase for the second messenger cyclic GMP-AMP (cGAS) and the cyclic GMP-AMP (cGAMP) receptor stimulator of interferon genes (STING) and the ciliary neurotrophic factor (CNTF)-STAT3 signaling axis can be engaged upon nerve injury to mediate neuroimmune reactions.4Wu J. Li X. Zhang X. Wang W. You X. What role of the cGAS-STING pathway plays in chronic pain?.Front. Mol. Neurosci. 2022; 15: 963206https://doi.org/10.3389/fnmol.2022.963206Crossref PubMed Scopus (2) Google Scholar,5Hu Z. Deng N. Liu K. Zhou N. Sun Y. Zeng W. CNTF-STAT3-IL-6 axis mediates neuroinflammatory cascade across Schwann cell-neuron-microglia.Cell Rep. 2020; 31: 107657https://doi.org/10.1016/j.celrep.2020.107657Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar Understanding and harnessing their regulatory functions in the repair program to its full powder have emerged as a viable therapeutic option. To search for the molecular targets in axon regeneration, Wang and colleagues carried out a functional screening utilizing the DRG replating assay.1Wang X. Yang C. Wang X. Miao J. Chen W. Zhou Y. Xu Y. An Y. Cheng A. Ye W. et al.Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axis.Neuron. 2022; 111https://doi.org/10.1016/j.neuron.2022.10.028Abstract Full Text Full Text PDF Scopus (1) Google Scholar Out of 84 pre-selected phosphatases, protein tyrosine phosphatase non-receptor type 2 (Ptpn2) was identified among 5 candidates, knockdown of which promoted axon regrowth. Of particular importance, RGCs showed more regenerating axons post nerve injury when PTPN2 was inhibited pharmacologically or abrogated genetically. Next, the authors went on to explore the signaling cascade that involves PTPN2. When Ptpn2 was deleted in DRGs, transcriptome analysis showed that the injury-induced genes were significantly enriched in the categories related to host defense responses such as induction of interferon-stimulated genes (ISGs). When testing the ligands that may enhance the axon regeneration of RGCs upon Ptpn2 deletion, they observed that interferon γ (IFNγ) showed robust phenotypes. Endogenous IFNγ can be detected in the vitreous humor, and knocking down the receptor subunit Ifngr1 or Ifngr2 suppressed Ptpn2 deletion-induced axon regeneration, supporting the important role of endogenously produced IFNγ. To understand how IFNγ may stimulate axonal regeneration, the RGCs were sorted following retrograded labeling of axons. ISGs showed the most prominent induction upon Ptpn2 deletion in the presence of exogenous IFNγ. When accessing the downstream signaling events, Ptpn2 deletion appeared to sustain phosphorylated STAT1 much longer than wild-type controls. Notably, investigations of CNTF and PTEN pathways show that their effector components STAT3 and mTOR functioned independently from IFNγR-STAT1 for axonal regeneration. When probing the interconnection between PTPN2, STAT1, and ISGs, the authors tested the involvement of the cGAS-STING pathway. cGAS and STING belong to the family of ISGs transcriptionally induced by interferons. cGAS senses double-stranded DNA (dsDNA) and synthesizes cGAMP, which binds to and activates STING.6Sun L. Wu J. Du F. Chen X. Chen Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.Science. 2013; 339: 786-791https://doi.org/10.1126/science.1232458Crossref PubMed Scopus (2496) Google Scholar Interestingly, cGAS was upregulated in a STAT1-dependent manner. Meanwhile, DNA damage was detectable in a small percentage of RGCs after nerve injury, but the percentage increased drastically upon Ptpn2 deletion even in the absence of injury. Further, cGAS or STING deletion blocked the regenerating effect mediated by Ptpn2 knockdown. Lastly, they turned back to the PNS to probe the IFNγ-STAT1 axis in axon regeneration. Interestingly, the mRNA and protein of IFNγ were highly inducible in axons by nerve injury. Further examination showed that IFNγ was locally translated in axons. Different from the CNS where neurons exhibited cGAS expression, cGAS was induced in Schwann cells and blood cells in the PNS. Those non-neuronal cells generated cGAMP and signaled to neuronal STING in a trans-cellular manner. Mechanistically, cGAS-STING activation regulated the production of regenerating associated genes (RAGs) and local microtubule dynamics to promote axon regeneration. Collectively, in the periphery, the neurons and non-neuronal cells are coordinated to promote axonal growth. In sum, Wang et al. have elucidated how innate immune signaling contributes to axon regeneration (Figure 1). Importantly, the findings have raised many unresolved questions and enlightened our pursuit of axon regeneration intervention. At present, CNS axon regrowth can be induced following modulation of pro-growth signaling pathways in injured neurons or alteration of extrinsic factors that inhibit axon re-extension, but few of them have achieved complete recovery. Multiple layers of antagonizing mechanisms seem to ensure axon regrowth quiescence. In this scope, neuron autonomous and non-autonomous mechanisms are to be exploited simultaneously to alter neuronal homeostasis and the tissue microenvironment when maximizing structural and functional recovery. In addition to traumatic injuries, neurodegenerative diseases are inflicting an expanding population including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). Intriguingly, axonal damages often precede soma degeneration and represent a key feature in neuron degeneration. Designing ways to promote axon regeneration stand as an immediate option. Admittedly, our current understanding of axon regeneration and neuroimmune response is limited and perplexing. Taking the cGAS-STING pathway as an example, mice lacking STING exhibit hypersensitivity to nociceptive stimuli in the sensory neurons7Donnelly C.R. Jiang C. Andriessen A.S. Wang K. Wang Z. Ding H. Zhao J. Luo X. Lee M.S. Lei Y.L. Maixner W. Ko M.C. Ji R.R. STING controls nociception via type I interferon signalling in sensory neurons.Nature. 2021; 591: 275-280https://doi.org/10.1038/s41586-020-03151-1Crossref PubMed Scopus (51) Google Scholar; loss of functional STING protects mice from α-synuclein pre-formed fibril (α-Syn PFF)-induced motor deficits and dopaminergic neuron loss8Hinkle J.T. Patel J. Panicker N. Karuppagounder S.S. Biswas D. Belingon B. Chen R. Brahmachari S. Pletnikova O. Troncoso J.C. Dawson V.L. Dawson T.M. STING mediates neurodegeneration and neuroinflammation in nigrostriatal alpha-synucleinopathy.Proc. Natl. Acad. Sci. USA. 2022; 119e2118819119https://doi.org/10.1073/pnas.2118819119Crossref PubMed Scopus (14) Google Scholar; cGAS-STING activation serves as a critical determinant of TAR DNA-binding protein 43 (TDP-43)-associated pathology in ALS9Yu C.H. Davidson S. Harapas C.R. Hilton J.B. Mlodzianoski M.J. Laohamonthonkul P. Louis C. Low R.R.J. Moecking J. De Nardo D. et al.TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS.Cell. 2020; 183: 636-649.e18https://doi.org/10.1016/j.cell.2020.09.020Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar; and STING activation affects neuropathology in Niemann-Pick disease type C (NPC).10Chu T.T. Tu X. Yang K. Wu J. Repa J.J. Yan N. Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C.Nature. 2021; 596: 570-575https://doi.org/10.1038/s41586-021-03762-2Crossref PubMed Scopus (38) Google Scholar As a result, caution should be taken when tackling pathological conditions involving neuroinflammation. Reinvigorating the axonal regeneration program while at the same time restraining detrimental consequences remains a daunting challenge and a unique opportunity. This work was supported by the National Natural Science Foundation (32225019) and the Beijing Natural Science Foundation (5222010). The work was also supported by the Center for Life Sciences, the Institute for Immunology, and School of Medicine at Tsinghua University. The authors declare no competing interests. Driving axon regeneration by orchestrating neuronal and non-neuronal innate immune responses via the IFNγ-cGAS-STING axisWang et al.NeuronNovember 11, 2022In BriefThe neural innate immune responses for axon regeneration is not well understood. Wang and Yang et al. demonstrate that activating the immune signaling IFNγ-cGAS-STING axis promotes axon regeneration in both the PNS and the CNS, uncovering a role for the antiviral machinery in neural repair. Full-Text PDF Open Access